Combination anti-retroviral therapy (ART) has revolutionized the treatment and prevention of HIV-1 infection. Taken daily, ART prevents and suppresses the infection. However, ART interruption almost invariably leads to rebound viremia in infected individuals due to a long-lived latent reservoir of integrated proviruses. Therefore, ART must be administered on a life-long basis. Here we review recent preclinical and clinical studies suggesting that immunotherapy may be an alternative or an adjuvant to ART because, in addition to preventing new infections, anti-HIV-1 antibodies clear the virus, directly kill infected cells and produce immune complexes that can enhance host immunity to the virus.
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Bournazos, S., Wang, T. T., Dahan, R., Maamary, J. & Ravetch, J. V. Signaling by antibodies: recent progress. Annu. Rev. Immunol. 35, 285–311 (2017).
Kaplon, H. & Reichert, J. M. Antibodies to watch in 2019. MAbs 11, 219–238 (2019).
Wei, X. et al. Antibody neutralization and escape by HIV-1. Nature 422, 307–312 (2003).
Richman, D. D., Wrin, T., Little, S. J. & Petropoulos, C. J. Rapid evolution of the neutralizing antibody response to HIV type 1 infection. Proc. Natl Acad. Sci. USA 100, 4144–4149 (2003).
Buchacher, A. et al. Generation of human monoclonal antibodies against HIV-1 proteins; electrofusion and Epstein-Barr virus transformation for peripheral blood lymphocyte immortalization. AIDS Res. Hum. Retroviruses 10, 359–369 (1994).
Burton, D. R. et al. Efficient neutralization of primary isolates of HIV-1 by a recombinant human monoclonal antibody. Science 266, 1024–1027 (1994).
Trkola, A. et al. Human monoclonal antibody 2G12 defines a distinctive neutralization epitope on the gp120 glycoprotein of human immunodeficiency virus type 1. J. Virol. 70, 1100–1108 (1996).
Zwick, M. B. et al. Broadly neutralizing antibodies targeted to the membrane-proximal external region of human immunodeficiency virus type 1 glycoprotein gp41. J. Virol. 75, 10892–10905 (2001).
Gorny, M. K. et al. Neutralization of diverse human immunodeficiency virus type 1 variants by an anti-V3 human monoclonal antibody. J. Virol. 66, 7538–7542 (1992).
Trkola, A. et al. Delay of HIV-1 rebound after cessation of antiretroviral therapy through passive transfer of human neutralizing antibodies. Nat. Med. 11, 615–622 (2005).
Mehandru, S. et al. Adjunctive passive immunotherapy in human immunodeficiency virus type 1-infected individuals treated with antiviral therapy during acute and early infection. J. Virol. 81, 11016–11031 (2007).
Scheid, J. F. et al. A method for identification of HIV gp140 binding memory B cells in human blood. J. Immunol. Methods 343, 65–67 (2009).
Klein, F. et al. Antibodies in HIV-1 vaccine development and therapy. Science 341, 1199–1204 (2013).
West, A. P. Jr. et al. Structural insights on the role of antibodies in HIV-1 vaccine and therapy. Cell 156, 633–648 (2014).
Walker, L. M. & Burton, D. R. Passive immunotherapy of viral infections: ‘super-antibodies’ enter the fray. Nat. Rev. Immunol. 18, 297–308 (2018).
Mascola, J. R. & Haynes, B. F. HIV-1 neutralizing antibodies: understanding nature’s pathways. Immunol. Rev. 254, 225–244 (2013).
Gama, L. & Koup, R. A. New-generation high-potency and designer antibodies: role in HIV-1 treatment. Annu. Rev. Med. 69, 409–419 (2018).
Wu, X. et al. Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science 329, 856–861 (2010).
Scheid, J. F. et al. Sequence and structural convergence of broad and potent HIV antibodies that mimic CD4 binding. Science 333, 1633–1637 (2011).
Rudicell, R. S. et al. Enhanced potency of a broadly neutralizing HIV-1 antibody in vitro improves protection against lentiviral infection in vivo. J. Virol. 88, 12669–12682 (2014).
Huang, J. et al. Identification of a CD4-binding-site antibody to HIV that evolved near-pan neutralization breadth. Immunity 45, 1108–1121 (2016).
Mouquet, H. et al. Complex-type N-glycan recognition by potent broadly neutralizing HIV antibodies. Proc. Natl Acad. Sci. USA 109, E3268–E3277 (2012).
Walker, L. M. et al. Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature 477, 466–470 (2011).
Huang, J. et al. Broad and potent neutralization of HIV-1 by a gp41-specific human antibody. Nature 491, 406–412 (2012).
Kwon, Y. D. et al. Optimization of the solubility of HIV-1-neutralizing antibody 10E8 through somatic variation and structure-based design. J. Virol. 90, 5899–5914 (2016).
Sok, D. et al. Recombinant HIV envelope trimer selects for quaternary-dependent antibodies targeting the trimer apex. Proc. Natl Acad. Sci. USA 111, 17624–17629 (2014).
Doria-Rose, N. A. et al. Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies. Nature 509, 55–62 (2014).
Emini, E. A. et al. Prevention of HIV-1 infection in chimpanzees by gp120 V3 domain-specific monoclonal antibody. Nature 355, 728–730 (1992).
Mascola, J. R. et al. Protection of Macaques against pathogenic simian/human immunodeficiency virus 89.6PD by passive transfer of neutralizing antibodies. J. Virol. 73, 4009–4018 (1999).
Mascola, J. R. et al. Protection of macaques against vaginal transmission of a pathogenic HIV-1/SIV chimeric virus by passive infusion of neutralizing antibodies. Nat. Med. 6, 207–210 (2000).
Shibata, R. et al. Generation of a chimeric human and simian immunodeficiency virus infectious to monkey peripheral blood mononuclear cells. J. Virol. 65, 3514–3520 (1991).
Li, J., Lord, C. I., Haseltine, W., Letvin, N. L. & Sodroski, J. Infection of cynomolgus monkeys with a chimeric HIV-1/SIVmac virus that expresses the HIV-1 envelope glycoproteins. J. Acquir. Immune Defic. Syndr. 5, 639–646 (1992).
Pal, R. et al. Characterization of a simian human immunodeficiency virus encoding the envelope gene from the CCR5-tropic HIV-1 Ba-L. J. Acquir. Immune Defic. Syndr. 33, 300–307 (2003).
Gautam, R. et al. Pathogenicity and mucosal transmissibility of the R5-tropic simian/human immunodeficiency virus SHIV(AD8) in rhesus macaques: implications for use in vaccine studies. J. Virol. 86, 8516–8526 (2012).
Parren, P. W. et al. Antibody protects macaques against vaginal challenge with a pathogenic R5 simian/human immunodeficiency virus at serum levels giving complete neutralization in vitro. J. Virol. 75, 8340–8347 (2001).
Nishimura, Y. et al. Determination of a statistically valid neutralization titer in plasma that confers protection against simian-human immunodeficiency virus challenge following passive transfer of high-titered neutralizing antibodies. J. Virol. 76, 2123–2130 (2002).
Shingai, M. et al. Passive transfer of modest titers of potent and broadly neutralizing anti-HIV monoclonal antibodies block SHIV infection in macaques. J. Exp. Med. 211, 2061–2074 (2014).
Huang, Y. et al. Modeling cumulative overall prevention efficacy for the VRC01 phase 2b efficacy trials. Hum. Vaccin. Immunother. 14, 2116–2127 (2018).
Patel, P. et al. Estimating per-act HIV transmission risk: a systematic review. AIDS 28, 1509–1519 (2014).
Hessell, A. J. et al. Effective, low-titer antibody protection against low-dose repeated mucosal SHIV challenge in macaques. Nat. Med. 15, 951–954 (2009).
Gautam, R. et al. A single injection of anti-HIV-1 antibodies protects against repeated SHIV challenges. Nature 533, 105–109 (2016).
Moldt, B. et al. A nonfucosylated variant of the anti-HIV-1 monoclonal antibody b12 has enhanced FcγRIIIa-mediated antiviral activity in vitro but does not improve protection against mucosal SHIV challenge in macaques. J. Virol. 86, 6189–6196 (2012).
Ko, S. Y. et al. Enhanced neonatal Fc receptor function improves protection against primate SHIV infection. Nature 514, 642–645 (2014).
Gautam, R. et al. A single injection of crystallizable fragment domain-modified antibodies elicits durable protection from SHIV infection. Nat. Med. 24, 610–616 (2018).
Hinton, P. R. et al. An engineered human IgG1 antibody with longer serum half-life. J. Immunol. 176, 346–356 (2006).
Poignard, P. et al. Neutralizing antibodies have limited effects on the control of established HIV-1 infection in vivo. Immunity 10, 431–438 (1999).
Klein, F. et al. HIV therapy by a combination of broadly neutralizing antibodies in humanized mice. Nature 492, 118–122 (2012).
Horwitz, J. A. et al. HIV-1 suppression and durable control by combining single broadly neutralizing antibodies and antiretroviral drugs in humanized mice. Proc. Natl Acad. Sci. USA 110, 16538–16543 (2013).
Diskin, R. et al. Restricting HIV-1 pathways for escape using rationally designed anti-HIV-1 antibodies. J. Exp. Med. 210, 1235–1249 (2013).
Klein, F. et al. Enhanced HIV-1 immunotherapy by commonly arising antibodies that target virus escape variants. J. Exp. Med. 211, 2361–2372 (2014).
Freund, N. T. et al. Coexistence of potent HIV-1 broadly neutralizing antibodies and antibody-sensitive viruses in a viremic controller. Sci. Transl. Med. 9, eaal2144 (2017).
Shingai, M. et al. Antibody-mediated immunotherapy of macaques chronically infected with SHIV suppresses viraemia. Nature 503, 277–280 (2013).
Barouch, D. H. et al. Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys. Nature 503, 224–228 (2013).
Halper-Stromberg, A. et al. Broadly neutralizing antibodies and viral inducers decrease rebound from HIV-1 latent reservoirs in humanized mice. Cell 158, 989–999 (2014).
Jaworski, J. P. et al. Neutralizing polyclonal IgG present during acute infection prevents rapid disease onset in simian-human immunodeficiency virus SHIVSF162P3-infected infant rhesus macaques. J. Virol. 87, 10447–10459 (2013).
Nishimura, Y. et al. Early antibody therapy can induce long-lasting immunity to SHIV. Nature 543, 559–563 (2017).
Borducchi, E. N. et al. Antibody and TLR7 agonist delay viral rebound in SHIV-infected monkeys. Nature 563, 360–364 (2018).
Vittecoq, D. et al. Passive immunotherapy in AIDS: a randomized trial of serial human immunodeficiency virus-positive transfusions of plasma rich in p24 antibodies versus transfusions of seronegative plasma. J. Infect. Dis. 165, 364–368 (1992).
Cavacini, L. A. et al. Phase I study of a human monoclonal antibody directed against the CD4-binding site of HIV type 1 glycoprotein 120. AIDS Res. Hum. Retroviruses 14, 545–550 (1998).
Armbruster, C. et al. A phase I trial with two human monoclonal antibodies (hMAb 2F5, 2G12) against HIV-1. AIDS 16, 227–233 (2002).
Armbruster, C. et al. Passive immunization with the anti-HIV-1 human monoclonal antibody (hMAb) 4E10 and the hMAb combination 4E10/2F5/2G12. J. Antimicrob. Chemother. 54, 915–920 (2004).
Caskey, M. et al. Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature 522, 487–491 (2015).
Lynch, R. M. et al. Virologic effects of broadly neutralizing antibody VRC01 administration during chronic HIV-1 infection. Sci. Transl. Med. 7, 319ra206 (2015).
Ledgerwood, J. E. et al. Safety, pharmacokinetics and neutralization of the broadly neutralizing HIV-1 human monoclonal antibody VRC01 in healthy adults. Clin. Exp. Immunol. 182, 289–301 (2015).
Caskey, M. et al. Antibody 10-1074 suppresses viremia in HIV-1-infected individuals. Nat. Med. 23, 185–191 (2017).
Lu, C. L. et al. Enhanced clearance of HIV-1-infected cells by anti-HIV-1 broadly neutralizing antibodies in vivo. Science 352, 1001–1004 (2016).
Schoofs, T. et al. HIV-1 therapy with monoclonal antibody 3BNC117 elicits host immune responses against HIV-1. Science 352, 997–1001 (2016).
Scheid, J. F. et al. HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption. Nature 535, 556–560 (2016).
Cohen, Y. Z. et al. Relationship between latent and rebound viruses in a clinical trial of anti-HIV-1 antibody 3BNC117. J. Exp. Med. 215, 2311–2324 (2018).
Bar, K. J. et al. Effect of HIV antibody VRC01 on viral rebound after treatment interruption. N. Engl. J. Med. 375, 2037–2050 (2016).
Cohen, Y. Z. et al. Neutralizing activity of broadly neutralizing anti-HIV-1 antibodies against Clade B clinical isolates produced in peripheral blood mononuclear cells. J. Virol. 92, e01883–17 (2018).
Bar-On, Y. et al. Safety and antiviral activity of combination HIV-1 broadly neutralizing antibodies in viremic individuals. Nat. Med. 24, 1701–1707 (2018).
Mendoza, P. et al. Combination therapy with anti-HIV-1 antibodies maintains viral suppression. Nature 561, 479–484 (2018).
Moldt, B. et al. Highly potent HIV-specific antibody neutralization in vitro translates into effective protection against mucosal SHIV challenge in vivo. Proc. Natl Acad. Sci. USA 109, 18921–18925 (2012).
Julg, B. et al. Broadly neutralizing antibodies targeting the HIV-1 envelope V2 apex confer protection against a clade C SHIV challenge. Sci. Transl. Med. 9, eaal1321 (2017).
Gaudinski, M. R. et al. Safety and pharmacokinetics of the Fc-modified HIV-1 human monoclonal antibody VRC01LS: A phase 1 open-label clinical trial in healthy adults. PLoS Med. 15, e1002493 (2018).
Gilbert, P. B. et al. Basis and statistical design of the passive HIV-1 antibody mediated prevention (AMP) test-of-concept efficacy trials. Stat. Commun. Infect. Dis. 9, 20160001 (2017).
Wagh, K. et al. Potential of conventional & bispecific broadly neutralizing antibodies for prevention of HIV-1 subtype A, C & D infections. PLoS Pathog. 14, e1006860 (2018).
Doria-Rose, N. A. et al. HIV-1 neutralization coverage is improved by combining monoclonal antibodies that target independent epitopes. J. Virol. 86, 3393–3397 (2012).
Kong, R. et al. Improving neutralization potency and breadth by combining broadly reactive HIV-1 antibodies targeting major neutralization epitopes. J. Virol. 89, 2659–2671 (2015).
Sengupta, S. & Siliciano, R. F. Targeting the latent reservoir for HIV-1. Immunity 48, 872–895 (2018).
Chun, T. W. et al. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 387, 183–188 (1997).
Lorenzi, J. C. et al. Paired quantitative and qualitative assessment of the replication-competent HIV-1 reservoir and comparison with integrated proviral DNA. Proc. Natl Acad. Sci. USA 113, E7908–E7916 (2016).
Hosmane, N. N. et al. Proliferation of latently infected CD4+ T cells carrying replication-competent HIV-1: potential role in latent reservoir dynamics. J. Exp. Med. 214, 959–972 (2017).
Wang, Z. et al. Expanded cellular clones carrying replication-competent HIV-1 persist, wax, and wane. Proc. Natl Acad. Sci. USA 115, E2575–E2584 (2018).
Walker, B. D. & Yu, X. G. Unravelling the mechanisms of durable control of HIV-1. Nat. Rev. Immunol. 13, 487–498 (2013).
Kalialis, L. V., Drzewiecki, K. T. & Klyver, H. Spontaneous regression of metastases from melanoma: review of the literature. Melanoma Res. 19, 275–282 (2009).
Koup, R. A. et al. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J. Virol. 68, 4650–4655 (1994).
Walker, B. D. et al. HIV-specific cytotoxic T lymphocytes in seropositive individuals. Nature 328, 345–348 (1987).
Deng, K. et al. Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations. Nature 517, 381–385 (2015).
Dhodapkar, K. M. et al. Selective blockade of inhibitory Fcgamma receptor enables human dendritic cell maturation with IL-12p70 production and immunity to antibody-coated tumor cells. Proc. Natl Acad. Sci. USA 102, 2910–2915 (2005).
Ribas, A. & Wolchok, J. D. Cancer immunotherapy using checkpoint blockade. Science 359, 1350–1355 (2018).
Margolis, D. M. & Archin , N. M. Proviral latency, persistent human immunodeficiency virus infection, and the development of latency reversing agents. J. Infect. Dis. 215, S111–S118 (2017).
Cohn, L. B. et al. Clonal CD4+ T cells in the HIV-1 latent reservoir display a distinct gene profile upon reactivation. Nat. Med. 24, 604–609 (2018).
Shan, L.et al. Transcriptional reprogramming during effector-to-memory transition renders CD4+ T cells permissive for latent HIV-1 infection. Immunity 47, 766–775 e763 2017).
Cockerham, L. R., Hatano, H. & Deeks, S. G. Post-treatment controllers: role in HIV “cure” research. Curr. HIV/AIDS Rep. 13, 1–9 (2016).
Namazi, G. et al. The control of HIV after antiretroviral medication pause (CHAMP) study: posttreatment controllers identified from 14 clinical studies. J. Infect. Dis. 218, 1954–1963 (2018).
Sáez-Cirión, A. et al. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study. PLoS Pathog. 9, e1003211 (2013).
Scott-Algaram, D. et al. Post-treatment controllers have particular NK cells with high anti-HIV capacity: VISCONTI study. Conference on Retroviruses and Opportunistic Infections, abstr. 52 (2015).
We thank members of the Klein and Nussenzweig laboratories for discussion. This work was supported by the NIH/National Institute of Allergy and Infectious Diseases Grant (U01AI129825), the Einstein-Rockefeller-CUNY Center for AIDS Research (1P30AI124414-01A1) and the BEAT-HIV Delaney grant UM1 AI126620 (M.C.); the Heisenberg-Program of the DFG (KL 2389/2-1), the European Research Council (ERC-StG639961) and the German Center for Infection Research (DZIF) (F.K.); the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD) grants OPP1092074 and OPP1124068 and the NIH grants 1UM1 AI100663 and R01AI-129795 (M.C.N.); and the Robertson fund.